CN101544572A - Ambroxol derivative and method for preparing same - Google Patents
Ambroxol derivative and method for preparing same Download PDFInfo
- Publication number
- CN101544572A CN101544572A CN200810084145A CN200810084145A CN101544572A CN 101544572 A CN101544572 A CN 101544572A CN 200810084145 A CN200810084145 A CN 200810084145A CN 200810084145 A CN200810084145 A CN 200810084145A CN 101544572 A CN101544572 A CN 101544572A
- Authority
- CN
- China
- Prior art keywords
- amino
- protecting group
- compound
- tertbutyloxycarbonyl
- agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to an ambroxol derivative and a method for preparing the same, in particular to the ambroxol derivative of a formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and application thereof in medical treatment. In the formula (I), R is as defined as description.
Description
Technical field
The present invention relates to a kind of ambroxol derivative and preparation method thereof, with itself and application in expelling phlegm drugs.
Background technology
Transbroncho (Ambroxol), chemistry is called trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin, it is expelling phlegm drugs commonly used at present, its toxicity is low, determined curative effect, and phlegm-dispelling functions is stronger than bromhexine, its preparation method and pharmacological action are delivered on U.S. Pat 3536713, and this medicine is used for clinical the form with hydrochloride in 1984.Its clinical application is at Respiration51 Suppl.1, delivers on 37 (1987).At present the hydrochloride Transbroncho is widely used in the treatment respiratory tract system disease in states such as many countries such as the U.S., Britain, Germany, Japan, and clinical effectiveness is good, almost non-toxic side effect.Clinical trial proves: these product can be regulated slurries and mucous secretion, promote lung to show the synthetic of active substance, strengthen fibre swing, make expectoration become easy.These product also can increase the respiratory tract liquid measure, reduce mucus secretion, can promote the secretion and the segmental bronchus ciliary movement of pulmonary surfactant, make phlegm be easy to expectoration.Ambroxol HCl can improve the lung functions index, the prevention respiratory tract infection.Ambroxol HCl is widely used in the acute and chronic respiratory tract disease with sputum diacrisis and expectoration dysfunction clinically, the for example prophylactic treatment and the assisting therapy of acute/chronic bronchitis, asthmatic bronchitis, bronchiectasis and san bronchial asthma, pulmonary surgery patient's postoperative pulmonary complication, the thick sputum that pulmonary tuberculosis etc. cause, dys-expectoration, and the treatment of premature infant and congenital alveolar dysplasia.
Ambroxol hydrochloride oral absorbs rapidly, eliminates transformation period 2-3 hour, and its preparation mainly contains tablet, sustained-release micro-pill capsules, solution, syrup, aqueous injection and other compound preparation, but because Ambroxol HCl water-soluble not ideal are used its preparation and clinical application all is subjected to certain limitation.
The present invention is by discovering, hydroxyl in the Transbroncho is become ester by covalent linkage with carboxyl in the amino acid, resulting derivative and salt thereof have extraordinary water-soluble, and in human body, can be converted into Transbroncho rapidly, bioavailability is Transbroncho ideal prodrug than the Ambroxol HCl height.
Summary of the invention
The object of the present invention is to provide the derivative of Transbroncho, or its pharmacy acceptable salt, have structure as shown in the formula I:
Wherein, R is an amino acid, and becomes ester by its carboxyl with the Transbroncho hydroxyl, and described amino acid is preferably L-L-Ala and L-Xie Ansuan.Described salt is a part or two molecules or three fens alites, preferably 2 fens alites that the amino of compound shown in various organic acids or mineral acid and the structure I forms.Described organic acid such as methylsulfonic acid, tosic acid, toxilic acid, tartrate, methylsulfonic acid preferably, described mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid etc.
Medicine water-soluble very big to the influence of its oral administration biaavailability, Ambroxol HCl is water-soluble undesirable, and that the compound of said structure has is well water-soluble.Test shows that the oral administration biaavailability of above-claimed cpd and blood peak concentration of drug are than the Ambroxol HCl height.
On the one hand; another object of the present invention is to provide a kind of method for preparing formula I compound of the present invention; particularly; the invention provides a kind of method for preparing formula I compound of the present invention; be initiator wherein with formula II compound; with the condensation in the presence of condensing agent and catalyzer of the protected amino acid of amino, through the condensation product of reductive agent reduction gained, deaminize protecting group in the presence of deprotection agent again.
Amino protected amino acid is example with the GP-NH-L-L-Ala; with the condensation in the presence of condensing agent and catalyzer of formula II compound; condensation product through reductive agent reduction gained; deaminize protecting group in the presence of deprotection agent again, wherein PG is selected from tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or 4-methoxy-benzyl.
Concrete implementation route is as follows:
Protective material herein is preferably tertbutyloxycarbonyl; Used condensing agent is N, N-dicyclohexyl carbimide (DCC) or 1-ethyl-3-(3-first aminopropyl)-carbodiimide hydrochloride (EDC-HCl); That better is DCC; Used catalyzer is 4-DMAP; Used reductive agent is KBH
4Or NaBH
4, KBH preferably
4The condition of deprotection base is an acidic conditions, preferably the mixing solutions of trifluoracetic acid and organic solvent.
On the other hand, a further object of the present invention is to provide a kind of method of preparation I compound, wherein, is initiator with the formula III compound, and in the presence of condensing agent and catalyzer, with the protected amino acid condensation of amino, the condenses of gained is sloughed protecting group.
Amino protected amino acid is example with the GP-NH-L-L-Ala, with the condensation in the presence of condensing agent and catalyzer of formula III compound, and deaminize protecting group in the presence of deprotection agent again.
Concrete implementation route is as follows:
Wherein,
PG is an amino protecting group, is selected from tertbutyloxycarbonyl, carbobenzoxy-(Cbz), 4-methoxy-benzyl, and wherein protective material is preferably tertbutyloxycarbonyl; Used condensing agent is N, N-dicyclohexyl carbimide (DCC) or 1-ethyl-3-(3-first aminopropyl)-carbodiimide hydrochloride (EDC-HCl), preferably DCC; Used catalyzer is 4-DMAP; The condition of deprotection base is an acidic conditions, preferably the mixing solutions of trifluoracetic acid and organic solvent.
Embodiment:
Present invention will be described in more detail for routine embodiment down, but can not be interpreted as limitation of the present invention.
Embodiment one
The L-L-Ala [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] the ester dimethanesulfonate
Embodiment is as follows:
The first step: trans-4-[(2-amino-3,5-dibromobenzene methyl)-the N-t-butoxycarbonyl amino] hexalin
Sodium hydroxide 0.16g (4mmol) is dissolved in the 10ml water, adds THF10ml, adds Transbroncho 1.134g (3mmol), be cooled to 0-5 ℃, drip tert-Butyl dicarbonate 0.87g (4mmol), dripped complete insulated and stirred 6 hours, reaction solution adds ethyl acetate 30ml and stirs, tell organic layer, washing, salt washing, dried over mgso, concentrate and desolvate, get oily matter 1.3g, ESI-MS (m/z): 501.01 ([M+Na]).
Second step: the N-tert-butoxycarbonyl-l-alanine [trans-4-[(2-amino-3,5-dibromobenzene methyl)-the N-t-butoxycarbonyl amino] hexalin] ester
Trans-4-[(2-amino-3,5-dibromobenzene methyl)-and the N-t-butoxycarbonyl amino] hexalin 3.0g (6.28mmol), N-tert-butoxycarbonyl-l-alanine 1.4g (7.5mmol) is dissolved in the 50ml dry methylene chloride, be cooled to 0-5 ℃, add N, N-dicyclohexyl carbimide 1.55g (7.5mmol) and 4-Dimethylamino pyridine 0.3g (2.5mmol), stirred 0.5 hour, reacting liquid filtering, filtrate washing, salt washing, dried over mgso, concentrate and desolvate, get colorless oil 4.0g, ESI-MS (m/z): 672.10 ([M+Na]).
The 3rd step: the L-L-Ala [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] the ester dimethanesulfonate
Above-mentioned oily matter is dissolved in the 30ml methylene dichloride, 20-25 ℃ drips the 10ml trifluoracetic acid down, drips to finish and stirs 3 hours, and reaction solution drips saturated sodium carbonate solution to pH=8, tell organic layer, water layer with the 30ml dichloromethane extraction once merges organic layer, washing, salt solution water, dried over mgso concentrates and desolvates, and resistates oily matter adds Virahol 20ml dissolving, drip methanesulfonic to pH=3, separate out solid, stir 1 hour after-filtration, the filter cake oven dry, recrystallization in methyl alcohol-ethanol, get white powder 3.2g, mp:240 ℃ (decomposition), ESI-MS (m/z): 450.03 ([M+H])
1H NMR (DMSO-d6,400M) δ: 1.40 (d, 3H), 1.52 (m, 4H), 2.06 (dd, 4H), 2.33 (s, 3H), 2.51 (s, 3H), 4.07 (m, 1H), 4.15 (s, 2H), 4.74 (m, 1H), 7.46 (d, 1H), 7.66 (d, 1H), 8.27 (brs, 2H)
Embodiment two
Embodiment is as follows:
The first step: the N-tert-butoxycarbonyl-l-alanine [trans-4-[(2-amino-3,5-dibromobenzene methylene radical) amino] hexalin] ester
Trans-4-[(2-amino-3,5-dibromobenzene methylene radical) amino] hexalin 3g (8mmol), N-tert-butoxycarbonyl-l-alanine 1.89g (10mmol) is dissolved in the 20ml dry methylene chloride, be cooled to 0-5 ℃, add N, N-dicyclohexyl carbimide 2.06g (10mmol) and 4-Dimethylamino pyridine 0.36g (3mmol), stirred 0.5 hour, reacting liquid filtering, filtrate washing, salt washing, dried over mgso, concentrate and desolvate, get colorless oil, add methyl alcohol 40ml, 0-5 ℃ of stirring, separate out solid, filter white solid 3.5g, mp:116-118 ℃.
Second step: the N-tert-butoxycarbonyl-l-alanine [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] ester
Above-mentioned product 4g is dissolved in the mixed solution of methyl alcohol 20ml and tetrahydrofuran (THF) 10ml, adds POTASSIUM BOROHYDRIDE 0.8g in three batches under 5-10 ℃, finishes and stirs 1 hour, reaction solution is in 30 ℃ of pressure reducing and steaming methyl alcohol, resistates adds ethyl acetate 30ml and water 30ml, tells organic layer, and water layer extracts with ethyl acetate 20ml, merge organic layer, washing, salt washing, dried over mgso, concentrate and desolvate, get oily matter 3.6g.
The 3rd step: the L-L-Ala [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] the ester dimethanesulfonate
Above-mentioned oily matter is dissolved in the 20ml methylene dichloride, 20-25 ℃ drips the 7ml trifluoracetic acid down, drip to finish and stirred 3 hours, reaction solution drips saturated sodium carbonate solution to pH=8, tells organic layer, water layer with the 20ml dichloromethane extraction once, merge organic layer, washing, salt washing, dried over mgso, concentrate and desolvate, resistates adds Virahol 20ml dissolving, drips methanesulfonic to pH=3, separate out solid, stir 1 hour after-filtration, filter cake oven dry, recrystallization in methyl alcohol-ethanol, get white powder 3.5g, fusing point and spectroscopic data are with method one.
Embodiment three
The L-Xie Ansuan [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] the ester dimethanesulfonate
Embodiment is as follows:
The first step: N-tertbutyloxycarbonyl-L-Xie Ansuan [trans-4-[(2-amino-3,5-dibromobenzene methylene radical) amino] hexalin] ester
Trans-4-[(2-amino-3,5-dibromobenzene methylene radical) amino] hexalin 3g (8mmol), N-tertbutyloxycarbonyl-L-Xie Ansuan 2.17g (10mmol) is dissolved in the 20ml dry methylene chloride, be cooled to 0-5 ℃, add N, N-dicyclohexyl carbimide 2.06g (10mmol) and 4-Dimethylamino pyridine 0.36g (3mmol) stirred 0.5 hour, reacting liquid filtering, the filtrate washing, salt washing, dried over mgso, concentrate and desolvate, get colorless oil 4.0g.
Second step: N-tertbutyloxycarbonyl-L-Xie Ansuan [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] ester
Above-mentioned oily matter is dissolved in the mixed solution of methyl alcohol 20ml and tetrahydrofuran (THF) 10ml, adds POTASSIUM BOROHYDRIDE 0.8g in three batches under 5-10 ℃, finishes and stirs 1 hour, reaction solution is in 30 ℃ of pressure reducing and steaming methyl alcohol, resistates adds ethyl acetate 30ml and water 30ml, tells organic layer, and water layer extracts with ethyl acetate 20ml, merge organic layer, washing, salt washing, dried over mgso, concentrate and desolvate, get oily matter 3.8g.
The 3rd step: the L-Xie Ansuan [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] the ester dimethanesulfonate
Above-mentioned oily matter is dissolved in the 20ml methylene dichloride, 20-25 ℃ drips the 7ml trifluoracetic acid down, drips to finish and stirs 3 hours, and reaction solution drips saturated sodium carbonate solution to pH=8, tell organic layer, water layer with the 20ml dichloromethane extraction once merges organic layer, washing, the salt washing, dried over mgso concentrates and desolvates, and resistates adds Virahol 20ml dissolving, drip methanesulfonic to pH=3, separate out solid, stir 1 hour after-filtration, the filter cake oven dry, recrystallization in methyl alcohol-ethanol, get white powder 3.3g, mp:248-250 ℃ (decomposition), ESI-MS (m/z): 478.03 ([M+H])
1HNMR (DMSO-d6,400M) δ: 0.96-1.05 (m, 7H), 1.53 (m, 4H), 2.15 (dd, 4H), 2.34 (s, 3H), 2.49 (s, 3H), 3.88 (s, 1H), 4.15 (s, 2H), 4.78 (m, 2H), 7.46 (d, 1H), 7.65 (d, 1H), 8.27 (brs, 2H)
Embodiment four
L-L-Ala [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] preparation of ester dimethanesulfonate powder injection
Embodiment is as follows:
Raw material:
The L-L-Ala is [trans-4-
[(2-amino-3,5-dibromobenzene methyl) amino] hexalin]
Ester dimethanesulfonate 50g
N.F,USP MANNITOL 80g
The L-L-Ala is [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] ester dimethanesulfonate 50g adds the dissolving of an amount of water for injection, N.F,USP MANNITOL 80g adds an amount of water for injection dissolving, two solution are mixed, add injection and be diluted with water to 2000ml, filter, be loaded in the vial, send in the freeze drying box lyophilize.
Experimental example five
L-L-Ala [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] preparation of ester dimethanesulfonate liquid drugs injection
Raw material:
The L-L-Ala is [trans-4-
[(2-amino-3,5-dibromobenzene methyl) amino] hexalin]
Ester dimethanesulfonate 50g
Sodium-chlor 18g
Water for injection 2000ml
Take by weighing sodium-chlor, the water for injection that adds cumulative volume amount about 85%, stirring and dissolving, adding L-L-Ala is [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] the ester dimethanesulfonate, stirring makes it dissolving, adds the injection water to total amount, after stirring evenly, filter, inflated with nitrogen, embedding, 100 ℃ of flowing steam sterilizations.
Experimental example six
L-Xie Ansuan [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] preparation of ester dimethanesulfonate tablet
Raw material:
L-Xie Ansuan [trans-4
-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin]
Ester dimethanesulfonate 30g
Starch 60g
Microcrystalline Cellulose 20g
Secondary calcium phosphate 20g
8% polyvinylpyrrolidone is an amount of
Magnesium Stearate 0.9g
The L-Xie Ansuan is [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] ester two methylsulfonic acids, starch, Microcrystalline Cellulose, secondary calcium phosphate mix, add the 8% polyvinylpyrrolidone aqueous solution and make softwood, granulate with 20 order nylon mesh, 55-60 ℃ of drying adds Magnesium Stearate, through the whole grain of 20 eye mesh screens, mixing is used the tabletting machine compressing tablet.
Experimental example seven
L-Xie Ansuan [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] preparation of ester dimethanesulfonate oral liquid
Raw material:
The L-Xie Ansuan [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] ester diformazan sulphur
Hydrochlorate 30g
Propylene glycol 4g
Glycerine 2g
Sodium alginate 2g
Sucrose 10g
Sodium Benzoate 0.1
Citric acid 1.5g
Essence is an amount of
Pure water 100g
Behind Transbroncho acetyl-cysteine salt and auxiliary material adding pure water, stirring and dissolving, packing, promptly.
Embodiment eight
Solubility experiment
Accurately weighing L-L-Ala is [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] the ester dimethanesulfonate, the L-Xie Ansuan is [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] ester dimethanesulfonate and Ambroxol HCl, under 25-30 ℃, add in the quantitative distilled water of pH=7 until solid in batches and all dissolve and obtain settled solution, record dissolubility data and see the following form:
| Compound | Solubleness (mg/ml) |
| The L-L-Ala [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] the ester dimethanesulfonate | >500 |
| The L-Xie Ansuan [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] the ester dimethanesulfonate | >500 |
| Ambroxol HCl | 13 |
Embodiment nine
The bioavailability test
10 healthy volunteers are oral respectively to be equivalent to L-L-Ala [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin of Transbroncho 60mg] ester dimethanesulfonate and Ambroxol HCl, measure the concentration of Transbroncho in the blood, the results are shown in following table:
| Compound | AUC 0-t(ng.h/ml, mean value) |
| The L-L-Ala [trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin] the ester dimethanesulfonate | 1017 |
| Ambroxol HCl | 868 |
Claims (16)
1, the compound shown in a kind of formula I, or its pharmacy acceptable salt
Wherein, R is an amino acid, and becomes ester by its carboxyl with the Transbroncho hydroxyl.
2. compound according to claim 1 is characterized in that R is L-L-Ala or L-Xie Ansuan.
3. method for preparing claim 1 or 2 arbitrary described compounds, it is characterized in that: with formula II compound is initiator,
With the condensation in the presence of condensing agent and catalyzer of the protected amino acid of amino; condensation product through reductive agent reduction gained; deaminize protecting group in the presence of deprotection agent again, wherein, amino protecting group is selected from tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or 4-methoxy-benzyl.
4. method according to claim 3 is characterized in that: described amino acid whose amino protecting group is a tertbutyloxycarbonyl.
5. method according to claim 3 is characterized in that: described condensing agent is N, N-dicyclohexyl carbimide or 1-ethyl-3-(3-first aminopropyl)-carbodiimide hydrochloride.
6. method according to claim 3 is characterized in that: described catalyzer is the 4-Dimethylamino pyridine.
7. method according to claim 3 is characterized in that: described reductive agent is KBH
4Or NaBH
4
8. method according to claim 3 is characterized in that: described deprotection agent is a trifluoracetic acid.
9. method for preparing claim 1 or 2 arbitrary described compounds, it is characterized in that: with the formula III compound is initiator,
In the presence of condensing agent and catalyzer, with the protected amino acid condensation of amino, the condenses of gained is sloughed protecting group,
Wherein, PG is an amino protecting group, is selected from tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or 4-methoxy-benzyl, and amino protecting group is selected from tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or 4-methoxy-benzyl.
10. according to the method for claim 9, it is characterized in that: the protecting group of described formula III compound is a tertbutyloxycarbonyl.
11. method according to claim 9 is characterized in that: described amino protecting group is a tertbutyloxycarbonyl.
12. method according to claim 9 is characterized in that: described condensing agent is N, N-dicyclohexyl carbimide or 1-ethyl-3-(3-first aminopropyl)-carbodiimide hydrochloride.
13. method according to claim 9 is characterized in that: described catalyzer is the 4-Dimethylamino pyridine.
14. method according to claim 9 is characterized in that: described deprotection agent is a trifluoracetic acid.
15. a pharmaceutical composition is characterized in that containing the treatment effective dose, as the compound as claimed in claim 1 and the pharmaceutically acceptable carrier of activeconstituents.
16. the purposes of compound as claimed in claim 1 in the preparation expelling phlegm drugs.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100841459A CN101544572B (en) | 2008-03-26 | 2008-03-26 | Ambroxol derivative and method for preparing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100841459A CN101544572B (en) | 2008-03-26 | 2008-03-26 | Ambroxol derivative and method for preparing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101544572A true CN101544572A (en) | 2009-09-30 |
| CN101544572B CN101544572B (en) | 2013-03-20 |
Family
ID=41191975
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008100841459A Expired - Fee Related CN101544572B (en) | 2008-03-26 | 2008-03-26 | Ambroxol derivative and method for preparing same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101544572B (en) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351720A (en) * | 2011-10-21 | 2012-02-15 | 南京理工大学 | Simple and efficient ambroxol synthesis method |
| CN103073439A (en) * | 2013-02-05 | 2013-05-01 | 山东罗欣药业股份有限公司 | Synthesis method of ambroxol hydrochloride compound |
| US9518050B2 (en) | 2012-12-18 | 2016-12-13 | Almirall, S.A. | Cyclohexyl and quinuclidinyl carbamate derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activity |
| US9562039B2 (en) | 2013-02-27 | 2017-02-07 | Almirall, S.A. | Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both β2 adrenergic receptor agonist and M3 muscarinic receptor antagonist activities |
| US9579316B2 (en) | 2013-07-25 | 2017-02-28 | Almirall, S.A. | Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both muscarinic receptor antagonist and β2 adrenergic receptor agonist activities |
| TWI572602B (en) * | 2011-11-11 | 2017-03-01 | 艾美羅有限公司 | New cyclohexylamine derivatives having β2 adrenergic agonist and m3 muscarinic antagonist activities |
| US9643961B2 (en) | 2010-05-13 | 2017-05-09 | Almirall, S.A. | Cyclohexylamine derivatives having β2 adrenergic antagonist and M3 muscarinic antagonist activities |
| US10005771B2 (en) | 2014-09-26 | 2018-06-26 | Almirall, S.A. | Bicyclic derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities |
| US10456390B2 (en) | 2013-07-25 | 2019-10-29 | Almirall, S.A. | Combinations comprising MABA compounds and corticosteroids |
| WO2021012698A1 (en) * | 2019-07-24 | 2021-01-28 | 成都施贝康生物医药科技有限公司 | Dibromobenzyl derivative, stereoisomer or salt thereof, and preparation method therefor and use thereof |
| CN112745251A (en) * | 2019-10-31 | 2021-05-04 | 华创合成制药股份有限公司 | Compound for eliminating phlegm and preparation method and application thereof |
| WO2022193368A1 (en) * | 2021-03-17 | 2022-09-22 | 成都施贝康生物医药科技有限公司 | Trans-amantadine derivative or salt thereof, and preparation method therefor, composition thereof and use thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3536713A (en) * | 1966-05-10 | 1970-10-27 | Boehringer Sohn Ingelheim | N-(hydroxy-cyclohexyl)-aminobenzylamines and the salts thereof |
| EP0505180A1 (en) * | 1991-03-22 | 1992-09-23 | Merck & Co. Inc. | High-content ibuprofen lysinate pharmaceutical formulation |
| CN1130354A (en) * | 1993-09-07 | 1996-09-04 | 普罗克特和廿保尔公司 | Compositions containing amino acid salt of propionic acid non-steroidal anti-inflammatory agent and at least one of decongestant an expectorant, an antihistamine and an antitussive |
| CN1454888A (en) * | 2002-04-29 | 2003-11-12 | 常州市第四制药厂 | Rapid-dissoved ambroxol salt and preparing method thereof |
| CN1699337A (en) * | 2004-05-20 | 2005-11-23 | 江苏豪森药业股份有限公司 | Ambroxol cysteine analogs and their preparation process and use thereof |
-
2008
- 2008-03-26 CN CN2008100841459A patent/CN101544572B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3536713A (en) * | 1966-05-10 | 1970-10-27 | Boehringer Sohn Ingelheim | N-(hydroxy-cyclohexyl)-aminobenzylamines and the salts thereof |
| EP0505180A1 (en) * | 1991-03-22 | 1992-09-23 | Merck & Co. Inc. | High-content ibuprofen lysinate pharmaceutical formulation |
| CN1130354A (en) * | 1993-09-07 | 1996-09-04 | 普罗克特和廿保尔公司 | Compositions containing amino acid salt of propionic acid non-steroidal anti-inflammatory agent and at least one of decongestant an expectorant, an antihistamine and an antitussive |
| CN1454888A (en) * | 2002-04-29 | 2003-11-12 | 常州市第四制药厂 | Rapid-dissoved ambroxol salt and preparing method thereof |
| CN1699337A (en) * | 2004-05-20 | 2005-11-23 | 江苏豪森药业股份有限公司 | Ambroxol cysteine analogs and their preparation process and use thereof |
Cited By (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9643961B2 (en) | 2010-05-13 | 2017-05-09 | Almirall, S.A. | Cyclohexylamine derivatives having β2 adrenergic antagonist and M3 muscarinic antagonist activities |
| CN102351720A (en) * | 2011-10-21 | 2012-02-15 | 南京理工大学 | Simple and efficient ambroxol synthesis method |
| TWI572602B (en) * | 2011-11-11 | 2017-03-01 | 艾美羅有限公司 | New cyclohexylamine derivatives having β2 adrenergic agonist and m3 muscarinic antagonist activities |
| US9757383B2 (en) | 2011-11-11 | 2017-09-12 | Almirall, S.A. | Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities |
| US10300072B2 (en) | 2011-11-11 | 2019-05-28 | Almirall, S.A. | Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities |
| US9518050B2 (en) | 2012-12-18 | 2016-12-13 | Almirall, S.A. | Cyclohexyl and quinuclidinyl carbamate derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activity |
| CN103073439A (en) * | 2013-02-05 | 2013-05-01 | 山东罗欣药业股份有限公司 | Synthesis method of ambroxol hydrochloride compound |
| CN103073439B (en) * | 2013-02-05 | 2013-10-16 | 山东罗欣药业股份有限公司 | Synthesis method of ambroxol hydrochloride compound |
| US9562039B2 (en) | 2013-02-27 | 2017-02-07 | Almirall, S.A. | Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both β2 adrenergic receptor agonist and M3 muscarinic receptor antagonist activities |
| US9579316B2 (en) | 2013-07-25 | 2017-02-28 | Almirall, S.A. | Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both muscarinic receptor antagonist and β2 adrenergic receptor agonist activities |
| US10456390B2 (en) | 2013-07-25 | 2019-10-29 | Almirall, S.A. | Combinations comprising MABA compounds and corticosteroids |
| US10005771B2 (en) | 2014-09-26 | 2018-06-26 | Almirall, S.A. | Bicyclic derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities |
| WO2021012698A1 (en) * | 2019-07-24 | 2021-01-28 | 成都施贝康生物医药科技有限公司 | Dibromobenzyl derivative, stereoisomer or salt thereof, and preparation method therefor and use thereof |
| JP2022542675A (en) * | 2019-07-24 | 2022-10-06 | チォンドウ シーベイカン バイオメディカル テクノロジー カンパニー リミテッド | Dibromobenzyl group derivative, its stereoisomer or its salt, production method and application |
| JP7344607B2 (en) | 2019-07-24 | 2023-09-14 | チォンドウ シーベイカン バイオメディカル テクノロジー カンパニー リミテッド | Dibromobenzyl group derivatives, stereoisomers thereof or salts thereof, methods for producing dibromobenzyl group derivatives, drugs for preventing and treating respiratory diseases, expectorants and drug compositions |
| US12006276B2 (en) | 2019-07-24 | 2024-06-11 | Chengdu Shibeikang Biomedical Technology Co., Ltd. | Dibromobenzyl derivative, stereoisomer or salt thereof, and preparation method and application of dibromobenzyl derivative |
| CN112745251A (en) * | 2019-10-31 | 2021-05-04 | 华创合成制药股份有限公司 | Compound for eliminating phlegm and preparation method and application thereof |
| WO2021082501A1 (en) * | 2019-10-31 | 2021-05-06 | 华创合成制药股份有限公司 | Expectorant compound and preparation method and use thereof |
| JP2023500101A (en) * | 2019-10-31 | 2023-01-04 | 華創合成制薬股▲ふん▼有限公司 | Expectorant compound, method of preparation and use thereof |
| CN112745251B (en) * | 2019-10-31 | 2023-10-27 | 华创合成制药股份有限公司 | Compound for treating phlegm and preparation method and application thereof |
| AU2020375675B2 (en) * | 2019-10-31 | 2023-11-09 | HC Synthetic Pharmaceutical Co., Ltd. | Expectorant compound and preparation method and use thereof |
| JP7393052B2 (en) | 2019-10-31 | 2023-12-06 | 華創合成制薬股▲ふん▼有限公司 | Expectorant compounds, their preparation and use |
| US11993561B2 (en) | 2019-10-31 | 2024-05-28 | HC Synthetic Pharmaceutical Co., Ltd. | Expectorant compound, preparation method thereof and use thereof |
| WO2022193368A1 (en) * | 2021-03-17 | 2022-09-22 | 成都施贝康生物医药科技有限公司 | Trans-amantadine derivative or salt thereof, and preparation method therefor, composition thereof and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101544572B (en) | 2013-03-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101544572B (en) | Ambroxol derivative and method for preparing same | |
| KR101473028B1 (en) | Drug for treatment of influenza | |
| CA2606207C (en) | Pharmaceutical composition | |
| CA2974395C (en) | Compounds and methods for preventing or treating sensory hair cell death | |
| WO2009140887A1 (en) | A scutellarin derivative, the preparing process, the pharmaceutical composition and the use thereof | |
| US20220280648A1 (en) | Design and efficient synthesis of lipid-fluorescein conjugates for car-t cell therapy | |
| CN101712676B (en) | Water soluble puerarin derivatives and preparation method and application thereof | |
| CN101289438A (en) | 3-(3'-hydroxyl)-butyl phthalide ester, and preparation thereof and uses | |
| CN109956975A (en) | Liver delivers Entecavir pro-drug nucleosides cyclic phosphate compound and application | |
| CN101195615A (en) | Salt of imidazole-carboxylic acid derivant, production method and pharmaceutical composition thereof | |
| CN101429185B (en) | Two-crystal type of substance of meletin, production method, medicament composition and uses thereof | |
| EP2767533A1 (en) | Derivative of butylphthalide and preparation method and use thereof | |
| CN103012345B (en) | Luteolin alpha crystal form substance, preparation method thereof as well as pharmaceutical composition and application thereof | |
| SG188472A1 (en) | Prodrugs of guanfacine | |
| CN101993417A (en) | Stable novel crystal form of dimemorfan phosphate | |
| CN102250066B (en) | Fasudil derivative and preparation method thereof | |
| CN101857622B (en) | Adenosine derivative, and preparation method and application thereof | |
| CN109422751A (en) | One kind has the degradation active compound of tyrosine protein kinase JAK3 | |
| RU2699669C1 (en) | Novel compositions of n-carbamoylmethyl-4-phenyl-2-pyrrolidone | |
| CN103058976B (en) | Quercetin alpha crystal-form substance, preparation method thereof, pharmaceutical composition thereof and purpose thereof | |
| CN111960978A (en) | Synthesis method and application of S-allyl-L-cysteine substituted tyrosol derivative with neuroprotective activity | |
| CN102241644B (en) | Alpha-azyl-3-aryl propionamido thiazole derivative, preparation method and purpose thereof | |
| CN109721557A (en) | Letrozole crystalline substance II type solid matter and preparation method and its pharmaceutical composition and purposes | |
| CN102126973A (en) | Meglumine compound of dibasic ester acid and preparation method and medicinal application thereof | |
| CN107118176B (en) | N-(5- benzyl thiazol-2-yl) morpholinyl amide and its medical usage |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: JIANGSU HANSOH MEDICAL GROUP CO.,LTD. Free format text: FORMER OWNER: LIANYUNGANG HENGBANG PHARMACEUTICAL TECHNOLOGY CO., LTD. Effective date: 20131113 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20131113 Address after: 222047 Lianyungang Development Zone, Jiangsu Patentee after: Jiangsu Hansoh Medical Group Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee before: Lianyungang Hengbang Pharmaceutical Technology Co., Ltd. |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160315 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. Address before: 222047 Lianyungang Development Zone, Jiangsu Patentee before: Jiangsu Hansoh Medical Group Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130320 Termination date: 20210326 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |